Cerium is a rare earth element of the lanthanide series whose oxide form has been extensively used as a catalyst in many industrial processes. Cerium oxide nanoparticles are currently being studied for use in solid oxide fuel cells and as catalysts in catalytic converters primarily based on unique properties of oxygen vacancies within the cerium oxide lattice. In addition to industrial uses, recent evidence reported in the literature suggests that ceria nanoparticles can scavenge radicals and act as potent antioxidants in cell culture models and animal studies. Cerium nanoparticles have shown lifespan extension in primary neuronal cultures as well as protection from radiation induced cell death by apoptosis. Although it is clear these nanoparticles are impacting the cell in a profound way, the molecular mechanism by which these nanoparticles act is not well understood. Our recent studies have uncovered a potential molecular mechanism for this protection. The aims of this application focus on elucidating the biophysical properties of vacancy engineered nanoparticles that result in this antioxidant activity. We will synthesize ceria nanoparticles that vary in size and oxidation state (Cerium in +3 versus +4 states). We will test these nanoparticles for their antioxidant potential in both biochemical assays as well as cell culture based experiments. We will test these particles using a well established culture model for aging, human lung fibroblasts. Once the biophysical properties that are responsible for this antioxidant activity are uncovered, we will optimize the synthesis of ceria nanoparticles so that future studies based on these can move to animal experiments to determine the efficacy of vacancy engineered nanoparticles to treat or even prevent disease. Previous studies have shown that treatment of human and animal cells in culture with vacancy engineered ceria nanoparticles results in increased lifespan of these cells. Our preliminary data have likely uncovered the molecular mechanism behind this protection. The proposed studies have the potential to produce safe nanoparticles that can be further tested for treatment of diseases that are related to elevated oxidative damage to tissues such as cardiovascular disease, Alzheimer's disease and cancer.